Inhibition of Lon protease by triterpenoids alters mitochondria and is associated to cell death in human cancer cells.

Oncotarget
Lara GibelliniAndrea Cossarizza

Abstract

Mitochondrial Lon protease (Lon) regulates several mitochondrial functions, and is inhibited by the anticancer molecule triterpenoid 2-cyano-3, 12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO), or by its C-28 methyl ester derivative (CDDO-Me). To analyze the mechanism of action of triterpenoids, we investigated intramitochondrial reactive oxygen species (ROS), mitochondrial membrane potential, mitochondrial mass, mitochondrial dynamics and morphology, and Lon proteolytic activity in RKO human colon cancer cells, in HepG2 hepatocarcinoma cells and in MCF7 breast carcinoma cells. We found that CDDO and CDDO-Me are potent stressors for mitochondria in cancer cells, rather than normal non-transformed cells. In particular, they: i) cause depolarization; ii) increase mitochondrial ROS, iii) alter mitochondrial morphology and proteins involved in mitochondrial dynamics; iv) affect the levels of Lon and those of aconitase and human transcription factor A, which are targets of Lon activity; v) increase level of protein carbonyls in mitochondria; vi) lead to intrinsic apoptosis. The overexpression of Lon can rescue cells from cell death, providing an additional evidence on the role of Lon in conditions of excessive stress load.

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Citations

Aug 3, 2019·European Journal of Immunology·Sara De BiasiMarcello Pinti
Jun 12, 2020·Journal of Clinical Medicine·Anna De GaetanoMarcello Pinti
Feb 23, 2020·Biological Chemistry·Yohsuke OhbaThomas Langer
Oct 13, 2017·European Journal of Immunology·Andrea CossarizzaJakob Zimmermann
May 10, 2020·The Journal of Biological Chemistry·Janin LautenschlägerGabriele S Kaminski Schierle
Nov 27, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Rebecca BorellaMarcello Pinti
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Methods Mentioned

BETA
flow cytometry
confocal microscopy
transfection
transfect
Protein Oxidation
Assay

Software Mentioned

CellEvent
TOPRO
Adobe Photoshop
FlowJo
ImageLab
ImageJ
Attune Cytometric

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